19-halo androstenes



3,101,357 Patented Aug. 20, 1963 awe-r Ill-HALO ANDROSTENES Albert Bowers, Mexico City, Mexico, assignor to Syntax Corporation, Panama, Panama, a corporation of Panama No Drawing. Filed June 12 1962, Ser. No. 201,803 Claims priority, application Mexico Mar. 9, 1962 12 Claims. (or. 260-3914 In the above formulas R and R each represent hydrogen or a hydrocarbon carboxylic acyl group of less than 12 carbon atoms; R represents hydrogen, a lower alkyl, lower alkenyl or lower alkinyl and X represents fluorine or chlorine.

The acyl group is derived from hydrocarbon carboxylic Roi , acids containing less than 12 carbon atoms which may be saturated or unstaurated, of straight, branched, cylic or cylic-aliphatic chain, aromatic and may be substituted by functional groups such as hydroxy, alltoxy containing up to 5 carbon atoms, acyloxy containing up to 12 carbon atoms, nitro, amino or halogen. Typical ester groups are the acetate, propionate, enanthate, benzoate, trimethylacetate, t-butylacetate, phenoxyacetate, cyclopentylpropionate, aminoacetate and fi-chloropropionate.

The compounds represented by the above formulas exhibit anabolic-androgenic activities and inhibit the production of pituitary gonadotrophic hormones and A.C.T.H. In addition, they have anti-estrogenic properties and lower the blood, liver and adrenal cholesterol levels. Furthermore, they are useful in the control of fertility and psychotic conditions and are appetite stimulants.

The novel compoundsof the present invention are prepared by the process illustrated by the following equations:

Ill

In the above formulas, R, R R and X have the same meaning as previously set torth.

In practicing the process outlined above, the starting A -androstene-3p,l9-diol-l7-one Sacetate (I), (produced in accordance with my copending application Serial No. 194,716, filed May 14, 1962, now US. Patent No. 3,065,228) is treated with an a-fluorinated amine, such as 2-chloro-l,1,2-trifluoro-triethylarnine, in a non-polar organic solvent, to produce l9-fluoro-A -androsten-3p-ol- 17-one acetate (II: X=fluorine).

Alternatively, upon conventional treatment of the starting compound (I) with tosyl chloride in pyridine, there is obtained the corresponding l9-tosylate which is treated with an alkali metal halide, such as lithium chloride or fluoride, or silver fluoride, in a suitable solvent, such as dimethylformamide or acetonitrile, thus atfording the corresponding l9-fluoro or chloro-A -androsten-3B-ol-17- one acetate (II: R=acetyl) which upon conventional saponification affords the corresponding 3 3-free alcohol (II: R=H).

Reduction of the 17-keto 3-acetates (II: R=acetyl) with a double metal hydride, such as sodium borohydride, aifords the corresponding l9-ha1o-A -androstene-3fi,17B- diol 3"8Cfiifli6 (III: R =R =H, R=acyl) which upon conventional saponification with a base yields the corresponding l9 halo A androstene 35,176 diol (III: R=R =8 =HL The l9-fluoro or chloro-M-androsten-Sfl-ol-17-one acetate (II) is treated with a lower (alkyl, alkenyl or alkinyl) magnesium halide, such as methyl magnesium bromide, vinyl magnesium bromide or ethinyl magnesium bromide, in a solvent inert to the reagent, e.g. ether, to produce the corresponding l9-halo-l7a-(alkyl, alkenyl or alkinyl)- A -androstene-3p,l7fi-diol [IIIz R=R =H, R =lower (alkyl, alkenyl or alkinyl)].

The secondary hydroxyls of the compounds of the present invention, namely the 3-B-hydroxyl group and the 17- hydroxyl group of the flat-unsubstituted derivatives are conventionally acylated in pyridine with an acylating agent, such as an anhydride derived from a hydrocarbon carboxylic acid of the type defined previously, thus affor-ding the corresponding acylates.

The tertiary hydroxyls of the compounds of the present invention, namely the 17,8-hydroxyl group of the 17:1- substituted derivatives, are conventionally estenified in the presence of p-itoluenesulfonic acid, with an acylating agent, e.g. acetic anhydride or caproic anhydride, to produce the corresponding l7-esters.

The following specific examples serve to illustrate, but are not intended to limit the scope of the present invention:

Example I To a solution of 5 g. of M-androstene-Iifl,l9-diol-l7- one S-acetate in 25 cc. of methylenechloride, were added 5 g. of 2-chloro-1,l,2-trifluoro triethyl amine (Yarovenlto et al. Journal of General Chemistry of the U.S.S.R., 2125, 29 (1959)). 15 cc. of the solvent were evaporated under anhydrous conditions and the resulting mixture was kept overnight at room temperature. The reaction mixture was evaporated to dryness and the residue was chromatographed on alumina, thus yielding compound No. 1, namely, 19fiuoro-A -androsten-3B-ol-l7-one acetate.

Example I] A solution of 3.4 g. of A -androstene-3fl,l9-diol-17-one S-acetate in 20 cc. of a mixture chloroform-pyridine 9:1 was cooled to 0 C. and mixed with 1.4 g. of tosyl chloride which was added in small portions. The reaction mixture was kept for 14 hours at 0 C. and then it was washed with dilute hydrochloric acid, water and sodium bicarbonate solution and the chloroform was evaporated under vacuum. The residue, consisted of the crude 19- tosylate. The crude product was dried in vacuum, dissolved in 29 cc. of acetonitrile and treated dropwise with 1.4 g. of silver fluoride dissolved in 3 cc. of water. After a short time, silver iodide started to separate leaving the 19-fluoro derivative in solution. The mixture was kept for 24 hours at room temperature and filtered. Concentration of the filtrate under vacuum gave a crude product which after crystallization from methanol-acetone yielded 19-fluoro-A -androsten-3B-ol-17-one acetate, identical with the final product of the foregoing example.

Example III A solution of 5 g. of A -androstene-3B,l9-diol-17-one 3-acetate in cc. of pyridine was cooled to 0 C. Under stirring there was added 1.3 g. of tosyl chloride, the mixture was kept for 16 hours at 0 C., diluted with 100 cc. of chloroform, washed with dilute hydrochloric acid, water, aqueous sodium bicarbonate solution and again with water, dried over anhydrous sodium sulfate and then evaporated to dryness under reduced pressure. Thus there was obtained the crude 19-tosylate of the starting compound.

A suspension of 10 g. of lithium fluoride in 50 cc. of dimethyl formamide was heated to boiling and then a solution of 2 g. of the crude tosylate in 10 cc. of dimethyl formamide was added. The mixture was refluxed for 5 hours, cooled and poured into water. The formed precipitate was filtered off and crystallized to give 19-fluoro-A androsten-3B-ol-l7-one acetate, identical with the final products of the above examples.

Example IV A -androstene-3p,19-diol-l7-one 3-acetate was treated following the procedure described in Example III, except that lithium chloride was used instead of lithium fluoride, thus afi'ording 19-chloro-A -androsten-3fl-ol-17-one acetate (compound No. 2).

Example V A solution of 2 g. of sodium borohydride in cc. of methanol was added with stirring to a solution of 2 g. of 19-fluoro-A -androsten--ol-17-one acetate (cpd. No. l) in cc. of tetrahydrofurarr. The mixture was kept at room temperature overnight, the excess reagent was decomposed by addition of acetic acid, the resulting solution concentrated to small volume in vacuo and diluted with water. The product was extracted with ethyl acetate, the extract washed with water, dried and evapo- A solution of 5 g. of 19-fluoro-A -androsten-35-01-17- one acetate (cpd. No. 1) in 250 cc. of thiophene-free benzene was treated with 27.5 cc. of 4N methylmagnesium bromide in ether and the mixture refluxed with the exclusion of moisture for 3 hours. The cooled mixture was cautiously treated with excess aqueous ammonium chloride solution and the product isolated by ethyl acetate extraction. The extract was washed with water, dried over anhydrous sodium [sulfate and evaporated to dryness.

Recrystallization from methylene chloride-hexane afforded 19-fluoro 17a. methyl-A -androstene-3fl,17B-diol (cpd. No. 5).

19-chloro-A -androsten-3fi-o1-17-one acetate (cpd. No. 2) was treated under exactly the same conditions, thus furnishing 19-chloro 17a methyl-M-androstene-35,175- diol (cpd. No. 6).

Example VII The compounds Nos. 1 and 2 were treated following the procedure described in Example VI, except that methylmagnesium bromide was substituted by vinyl magnesium bromide thus aflording respectively: 19-fluorol7a-vinyl-A -androstene-3B,17fl-diol (cpd. No. 7) and 19- chloro-17a-vinyl-A -androstene-3(3,1713-diol (cpd. No. 8).

Example VIII The compounds Nos. 1 and 2 were treated in accordance with Example VI, but using ethinyl magnesium bromide instead of methyl magnesium bromide, thus furnishing respectively: 19-fluoro-l7a-ethinyl-A -androstene- 3 3,17B-diol (cpd. No. 9) and 19-chloro-17a-ethiny1-A androstene-3;3,17fl-diol (cpd. No. 10).

Example IX Example X A mixture of 1 g. of 19-fiuoro-17a-methyl-A -androstene-3p,l7fl-diol (cpd. No. 5, 4 cc. of pyridine and 2 cc. of propionic anhydride was kept at room temperature overnight, poured into ice water, the formed precipitate was filtered, washed with water and dried. Crystallization from acetone-hexane gave 19-fluoro-l7a-methyl-A androstene-3B,l7B-diol 3-propionate (cpd. No. 13).

The compounds Nos. 6, 7, 8, 9 and 10 were treated (cpd. N0. 4) were treated following the procedure of Example X, thus affording respectively: 19-fluoro-A androstene 35,17 3 diol 3 acetate 17 propionate (cpd. No. 19) and 19-chloro-A -androstene-3 8,17B-diol 3-acctate-l7-propionate (cpd. No. 20).

Example XII To a solution of 5 g. of 19-fiuoro-17a-methyl-A androstene-3;3,17fi-diol 3-propionate (cpd. No. 13) in cc. of anhydrous benzene there were added 1 g. of ptoluene-sulfonic acid and 10 cc. of caproic anhydride and the mixture was allowed to stand for 24 hours at room temperature, poured into ice and water, and the resulting mixture stirred to etfect hydrolysis of the excess anhydride. The benzene layer was separated and washed with 10% sodium carbonate solution and water. Drying, evaporation and crystallization of the residue from ether-hexane produced 19-fluoro-17a-methyl-d androstene-3fl,17fi-diol 3-propionate-17-caproate (cpd. No. 21).

The compounds Nos. 14, 15, 16, 17 and 18 were treated in accordance with the above procedure, thus afiording respectively:

Cpd. No.

(22) 19-chloro- 1 7a-methyLA -androstene-35, 17 8- diol 3-propionate-17-caproate.

(23) 19-fiuoro-17a-vinyl-A -androstenc-3{3,17B-

diol 3-propionate-17'capr0ate.

(24) 19-chIoro-17u-vinyl-A -androstene-3fl,17 B- diol 3-propionate-17-caproate.

(25) l9-fluoro-17a-ethinyl-A androstene- 3B, 1 7f3-diol 3 -propionate- 1 7-caproate.

(26) 19-chloro-17a-ethinyl-A -androstene-3;3,17th

diol 3-propionate-17-caproate.

Example XIII The compounds Nos. 11 and 12 were treated following the procedure described in Example X, thus atfording respectively: 19-fluoro-A -androstene-3fi,17B-diol dipropionate (cpd. No. 27) and 19-chloro-A -androstene- 3fl,17B-diol dipropionate (cpd. No. 28).

Example XIV When the compounds Nos. 5 to 10, inclusive, were treated following the procedure of Example XII, there were obtained the corresponding dicaproates.

Example XV The compounds Nos. 1 and 2 were treated according to Example IX, thus alfording respectively: 19-fluoro-A androsten-3fi-o1-l7-one (cpd. No. 29) and IQ'ChIOIO-A androsten-3fi-ol-17-one (cpd. No. 30).

I claim:

1. A compound of the following formula:

l.. I]: IC

wherein R is selected from the group consisting of hydrogen and a hydrocarbon carboxylic acyl group of less than 12 carbon atoms; and X is a member of the group consisting of fluorine and chlorine.

1 1. 19-fluoroA -androsten-3B-ol-17-one.

l2. l9-chloro-A -androsten-3B-ol-17-0ne.

References Cited in the file of this patent Mills et al.: Chemistry and Industry, June 24, 1961, page 946. 

1. A COMPOUND OF THE FOLLOWING FORMULA:
 10. A COMPOUND OF THE FOLLOWING FORMULA: 3-(R-O-),17-(O=),19-X-ANDROSTANE WHEREIN R IS SELECTED FROM THE GROUP CONSISTING OF HYDROGEN AND A HYDROCARBON CARBOXYLIC ACYL GROUP OF LESS THAN 12 CARBON ATOMS; AND X IS A MEMBER OF THE GROUP CONSISTING OF FLUORINE AND CHLORINE. 